Researchers say they have found a strategy to overcome the limitations of haploidentical hematopoietic stem cell transplantation (HSCT).
To prevent the early, severe graft-versus-host disease (GVHD) associated with haploidentical HSCT, donor T cells reacting with recipient antigens are eliminated from the graft prior to transplant.
However, the depletion of T cells can lead to delayed immune reconstitution in the transplant recipient, which increases the risk of infection and death.
Results of a new study may help clinicians decrease those risks. The study showed that the infusion of specially engineered haploidentical donor T cells induced early reconstitution of post-HSCT immunity. These cells were also able to control GVHD and preserve a graft-versus-leukemia effect.
This study appeared in the May issue of The Lancet Oncology and was funded by the biotech company MolMed SpA.
Claudio Bordignon, MD, from the Raffaele Scientific Institute, Milan, Italy, and colleagues conducted this phase 1/2, multicenter, nonrandomized trial of haploidentical T-cell depleted HSCT in 50 high-risk leukemia patients in remission.
Of the 50 patients, 28 patients received T cells engineered to carry the herpes simplex thymidine kinase suicide gene (TK cells).
To prepare the TK cells, the researchers used the haploidentical donor T lymphocytes that were collected prior to mobilization with G-CSF or marrow harvesting of stem cells. The T lymphocytes were expanded in vitro and then transduced with the herpes simplex thymidine kinase suicide gene. This rendered the cells sensitive to the antiviral agent ganciclovir, which enabled the researchers to selectively eliminate the cells upon the development of GVHD.
Twenty-eight patients received a first dose of TK cells. If patients did not achieve immune reconstitution 30 days later, they received up to 3 additional monthly infusions of TK cells. Transplant recipients did not receive GVHD prophylaxis following TK cell infusion.
Twenty-two patients achieved immune reconstitution at a median time of 75 days after HSCT and 23 days following TK cell infusion. Immune reconstitution was dependent on the dose of TK cells.
A progressive decline in the number and severity of infectious complications occurred in patients with immune reconstitution. Patients without immune reconstitution continued to have more frequent and more severe infectious complications.
Nonrelapse mortality at 100 days posttransplant was lower in patients who achieved immune reconstitution than in those who did not, at 14% and 60%, respectively. The researchers said this was possibly due to protection from late infectious mortality.
Effective immune reconstitution did not increase the incidence of GVHD, the researchers said. Rates of GVHD were similar to rates reported in other studies. Ten patients developed grades 1 to 4 acute GVHD, and 1 patient developed chronic GVHD.
Dr Bordignon and colleagues said acute GVHD was directly associated with infiltration of the TK cells at affected lesions. The team was able to control acute GVHD by administering ganciclovir, thereby activating the suicide gene and eliminating the TK cells.